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Drug-resistant endothelial cells facilitate progression, EMT and chemoresistance in nasopharyngeal carcinoma via exosomes

机译:耐药内皮细胞通过外泌体促进鼻咽癌的进展,EMT和化学抑制剂

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摘要

Recent antitumor drug development has included investigation of a wide variety of anti-angiogenesis therapies. Because cancer cells in tumors require new blood vessels to grow and spread, they stimulate capillary proliferation from existing vessels as well as new vessel formation from endothelial precursor cells. Our previous findings suggested that drug resistance in mouse endothelial cells supported tumor growth, but the relationship between endothelial cells (ECs) and nasopharyngeal carcinoma (NPC) cells remained unclear. Exosomes are small membrane vesicles that are released by several cell types, including human microvascular ECs (HMECs). Exosomes carrying membrane and cytoplasmic constituents have been described as participants in a novel mechanism of cell-to-cell communication. In the present study, we investigated the mechanisms underlying the interactions between HMECs and NPC cells. We found that drug-resistant HMECs secreted small heterogeneous 40-100 nm vesicles, defined as exosomes. Co-incubation of NPC cells with doxorubicin-resistant (R-DOX) HMEC-derived exosomes resulted in promotion of their proliferation, migration, and chemoresistance, as well as changes in the expression of epithelial-mesenchymal transition (EMT) markers. These effects were significantly inhibited by treatment with GW4869 (an exosome inhibitor). We also found that GW4869 inhibited the stimulation of drug-resistant HMECs on NPC progression by modulating EMT in vivo. These data suggest that exosomes participate in a novel mechanism by which drug-resistant ECs enhance NPC progression.
机译:最近的抗肿瘤药物开发包括对各种抗血管生成疗法的调查。由于肿瘤中的癌细胞需要新的血管来生长和扩散,因此它们刺激现有血管的毛细血管增殖以及内皮前体细胞的新血管形成。我们以前的研究结果表明,小鼠内皮细胞中的耐药性支持肿瘤生长,但内皮细胞(ECS)和鼻咽癌(NPC)细胞之间的关系尚不清楚。外泌体是小膜囊泡,其由几种细胞类型释放,包括人类微血管ECS(HMEC)。携带膜和细胞质成分的外泌体已被描述为细胞对细胞通信的新机制的参与者。在本研究中,我们研究了HMECs和NPC细胞之间的相互作用的基础。我们发现耐药性HMECs分泌的小型异质40-100nm囊泡,定义为外来体。用多柔比蛋白素抗性(R-DOX)HMEC衍生的外泌体的NPC细胞的共培养导致促进其增殖,迁移和化学性,以及上皮 - 间充质转换(EMT)标记的表达的变化。通过用GW4869(外出抑制剂)治疗显着抑制了这些效果。我们还发现GW4869通过在体内调节EMT来抑制对NPC进展的耐药性HMEC的刺激。这些数据表明,外泌体参与耐药ECS增强NPC进展的新机制。

著录项

  • 来源
    《Cellular Signalling》 |2019年第2019期|共10页
  • 作者单位

    Guizhou Prov Peoples Hosp Guizhou Canc Ctr Dept Oncol 83 Zhongshan East Rd Guiyang 550003 Guizhou Peoples R China;

    GuiZhou Med Univ Affiliated Hosp Dept Surg Guiyang 550004 Guizhou Peoples R China;

    Guizhou Prov Peoples Hosp Guizhou Canc Ctr Dept Oncol 83 Zhongshan East Rd Guiyang 550003 Guizhou Peoples R China;

    Guizhou Prov Peoples Hosp Guizhou Canc Ctr Dept Oncol 83 Zhongshan East Rd Guiyang 550003 Guizhou Peoples R China;

    Guizhou Prov Peoples Hosp Guizhou Canc Ctr Dept Oncol 83 Zhongshan East Rd Guiyang 550003 Guizhou Peoples R China;

    Guizhou Prov Peoples Hosp Guizhou Canc Ctr Dept Oncol 83 Zhongshan East Rd Guiyang 550003 Guizhou Peoples R China;

    Guizhou Prov Peoples Hosp Guizhou Canc Ctr Dept Oncol 83 Zhongshan East Rd Guiyang 550003 Guizhou Peoples R China;

    Hop St Louis INSERM UMRS 1165 Paris 7 Paris France;

    Hop St Louis INSERM UMRS 1165 Paris 7 Paris France;

    Guizhou Prov Peoples Hosp Guizhou Canc Ctr Dept Oncol 83 Zhongshan East Rd Guiyang 550003 Guizhou Peoples R China;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞形态学;
  • 关键词

    Nasopharyngeal carcinoma; Drug resistance; Human microvascular endothelial cells (HMECs); Exosome;

    机译:鼻咽癌;耐药性;人体微血管内皮细胞(HMECs);外泌虫;

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